Therapeutic gas delivery device with pulsed and continuous flow control

ABSTRACT

Described are methods and devices for therapeutic or medical gas delivery that utilize at least one proportional control valve and at least one binary control valve. The proportional control valve may be in series with the binary control valve to provide a valve combination capable of pulsing therapeutic gas at different flow rates, depending on the setting of the proportional control valve. Alternatively, the proportional control valve and binary control valve may be in parallel flow paths.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/211,919, filed on Mar. 14, 2014, which claims the benefit under 35U.S.C. § 119(e) to U.S. Provisional Application No. 61/791,775, filedMar. 15, 2013, the entire contents of which are incorporated herein byreference in their entirety.

TECHNICAL FIELD

Embodiments of the present invention generally relate to the field oftherapeutic gas administration, particularly to devices and methods fornitric oxide delivery.

BACKGROUND

Nitric oxide (NO) is a gas that, when inhaled, acts to dilate bloodvessels in the lungs, improving oxygenation of the blood and reducingpulmonary hypertension. Because of this, nitric oxide is provided as atherapeutic gas in the inspiratory breathing gases for patients withpulmonary hypertension.

Some nitric oxide delivery devices utilize a proportional control valveto continuously flow therapeutic gas to provide an approximatelyconstant concentration of nitric oxide in the patient's inspiratorybreathing gas, based on a desired concentration set by a clinician.However, as the flow rate of breathing gas rapidly rises and fallswithin the inspiratory or expiratory phases, it becomes difficult tocontinuously provide a proportional ratio-metric dose of delivered NOgas dependent on inspired flow. This is particularly true at the low endof the NO flow range, such as when the NO set dose and ventilator flowrates result in a low NO demand and therefore a low therapeutic gasdemand.

Other nitric oxide delivery devices utilize one or more binary controlvalves to approximate an average constant concentration of nitric oxideby constantly pulsing through the binary control valves. These devicesalso have problems at the low end of the NO delivery range, and may haveproblems with response time when meeting the sudden increased NO flowdemand in response to a ventilator inspiratory phase.

Still other nitric oxide delivery devices administer a single pulse ofnitric oxide to the patient as the patient inhales spontaneously. Suchdevices often use a pressure or flow sensor known as a patient triggersensor to detect when a patient begins inspiration for a particularbreath and also to detect each phase of the patients' breath: i.e.inspiratory, expiratory, etc. These devices will generally use at leastone binary control valve to provide a constant flow of NO during thepulsing event, but have a limited dose range because dose amounts canonly be varied by varying the time that the binary control valve isopen.

Accordingly, there is a need for new methods and devices for delivery oftherapeutic gases such as NO-containing gases.

SUMMARY

Provided are methods and devices that utilize at least one binarycontrol valve (i.e. a constant flow valve) and at least one proportionalcontrol valve (i.e. a variable flow valve) to provide enhanced dosingranges for therapeutic gas administration.

One aspect of the present invention relates to a therapeutic gasdelivery device that comprises at least one binary control valve and atleast one proportional control valve. In one or more embodiments of thisaspect, the gas delivery device comprises an inlet to connect to asource of therapeutic gas, an outlet to connect to a device thatintroduces the therapeutic gas to a patient, at least one binary controlvalve in fluid communication with the inlet and outlet that delivers aconstant flow of the therapeutic gas, at least one proportional controlvalve in fluid communication with the inlet and outlet that delivers avariable flow of the therapeutic gas, and a control system that deliversthe therapeutic gas through one or more of the binary control valve andthe proportional control valve. The therapeutic gas may comprise nitricoxide or a nitric oxide-releasing agent, or may be another therapeuticgas as described herein.

According to one or more embodiments, the binary control valve and theproportional control valve are in series. This combination of the binarycontrol valve and the proportional control valve may provide pulses oftherapeutic gas at varying flow rates. In some embodiments, thetherapeutic gas delivery device further comprises a pressure sensor,wherein the proportional control valve is upstream of the pressuresensor and the pressure sensor is upstream of the binary control valve.

In one or more embodiments, the binary control valve and theproportional control valve are in parallel flow paths.

If multiple binary and/or proportional control valves are used, variouscombinations of valves in parallel and/or in series are possible. Oneparticular configuration can include multiple binary control valves inparallel, which may provide pulses of therapeutic gas at either the sameor different flow rates. In some embodiments, the ratio of the flow rateof the first binary control valve to the flow rate of the second binarycontrol valve is in the range from about 1:2 to about 1:10. In someembodiments, the control system delivers multiple pulses per breaththrough one or more of the first binary control valve and the secondbinary control valve.

According to one or more embodiments, the gas control system deliversthe therapeutic gas into a flow of breathing gas through one or more ofthe binary control valve and the proportional control valve to provide acombined flow of therapeutic gas and breathing gas with a substantiallyconstant concentration of therapeutic gas. In further embodiments, thebinary control valve and the proportional control valve are in parallelflow paths and the control system delivers a continuous flow oftherapeutic gas through the proportional control valve when atherapeutic gas demand is greater than or equal to 5% of a deliveryrange and delivers one or more pulses of therapeutic gas through thebinary control valve when the therapeutic gas demand is less than orequal to 1% of the delivery range. As described herein, othertherapeutic gas demands may be used to determine whether a binary valveor proportional valve is used.

The device that introduces the therapeutic gas to the patient may be influid communication with a ventilator, or the patient may be breathingspontaneously. Examples of devices that may be used to introduce thetherapeutic gas to the patient include a nasal cannula, endotrachealtube or a face mask.

In some embodiments, the control system provides a single pulse in apatient's breath through one or more of the binary control valve and theproportional control valve.

Another aspect of the present invention pertains to a therapeutic gasdelivery device that comprises a binary control valve and a variablepressure regulator. In various embodiments of this aspect, thetherapeutic gas delivery device comprises an inlet to connect to asource of therapeutic gas, an outlet to connect to a device thatintroduces the therapeutic gas to a patient, at least one binary controlvalve in fluid communication with the inlet and outlet that delivers aconstant flow of the therapeutic gas when the upstream pressure isconstant, at least one variable pressure controller in fluidcommunication with the binary control valve that varies the pressureupstream of the binary control valve, and a control system that deliversthe therapeutic gas through the binary control valve. The therapeuticgas may comprise nitric oxide or a nitric oxide-releasing agent.

According to one or more embodiments, the control system is incommunication with the variable pressure regulator and varies thepressure upstream of the binary control valve. In some embodiments, thevariable pressure controller comprises a proportional control valve anda pressure sensor.

As with other embodiments described herein, the system may comprisemultiple binary control valves, multiple proportional control valvesand/or multiple variable pressure regulators. In some embodiments, thedelivery system comprises a second binary control valve in parallel tothe first binary control valve. These two binary control valves mayprovide pulses of therapeutic gas at either the same or different flowrates. In some embodiments, the ratio of the flow rate of the firstbinary control valve to the flow rate of the second binary control valveis in the range from about 1:2 to about 1:10. In some embodiments, thecontrol system delivers multiple pulses per breath through one or moreof the first binary control valve and the second binary control valve.

Again, the device that introduces the therapeutic gas to the patient maybe in fluid communication with a ventilator, or the patient may bebreathing spontaneously. Examples of devices that may be used tointroduce the therapeutic gas to the patient include a nasal cannula,endotracheal tube or a face mask.

In some embodiments, the control system provides a single pulse in apatient's breath.

Yet another aspect of the present invention a method of administering atherapeutic gas to a patient comprising using any of therapeuticdelivery devices described herein. In some embodiments, the methodcomprises providing a therapeutic gas delivery device having at leastone binary control valve that delivers a constant flow of therapeuticgas and at least one proportional control valve that delivers a variableflow of the therapeutic gas and delivering therapeutic gas to thepatient during inspiration through one or more of the binary controlvalve and the proportional control valve. As with any of the embodimentsdescribed herein, the therapeutic gas includes, but is not limited to,nitric oxide or a nitric oxide-releasing agent.

In one or more embodiments, the binary control valve and theproportional control valve are in series such that the combination ofthe binary control valve and the proportional control valve may providepulses of therapeutic gas at varying flow rates.

In one or more embodiments, the binary control valve and theproportional control valve are in parallel flow paths.

Various embodiments provide that the therapeutic gas is delivered sothat the patient is administered a constant concentration of drug. Forexample, the method may further comprise measuring a flow of breathinggas and delivering the therapeutic gas in an amount substantiallyproportional to the flow of breathing gas.

In some embodiments, the binary control valve and the proportionalcontrol valve are in parallel flow paths and a continuous flow oftherapeutic gas is delivered through the proportional control valve whena therapeutic gas demand is greater than or equal to 5% of a deliveryrange and one or more pulses of therapeutic gas is delivered through thebinary control valve when the therapeutic gas demand is less than orequal to 1% of the delivery range.

In one or more embodiments, the therapeutic gas delivery device furthercomprises a second binary control valve in parallel to the first binarycontrol valve, which may deliver constant flow or pulses of therapeuticgas at the same or different flow rates. In some embodiments, the ratioof the flow rate of the first binary control valve to the flow rate ofthe second binary control valve is in the range from about 1:2 to about1:10.

One or more embodiments provide that the method further comprisessensing the beginning of the patient's inspiration and delivering one ormore pulses of therapeutic gas to the patient during inspiration. Insome embodiments, at least one pulse is delivered in the first half ofthe patient's inspiration.

In one or more embodiments, a first amount of therapeutic gas isdelivered to the patient in a first breath, and the method furthercomprises monitoring the patient's respiratory rate or changes in thepatient's respiratory rate and varying the quantity of therapeutic gasdelivered to the patient in one or more subsequent breaths based on themonitored respiratory rate or changes in the patient's respiratory rate.

The foregoing has outlined rather broadly certain features and technicaladvantages of the present invention. It should be appreciated by thoseskilled in the art that the specific embodiments disclosed may bereadily utilized as a basis for modifying or designing other structuresor processes within the scope present invention. It should also berealized by those skilled in the art that such equivalent constructionsdo not depart from the spirit and scope of the invention as set forth inthe appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

So that the manner in which the above recited features of the presentinvention can be understood in detail, a more particular description ofthe invention, briefly summarized above, may be had by reference toembodiments, some of which are illustrated in the appended drawings. Itis to be noted, however, that the appended drawings illustrate onlytypical embodiments of this invention and are therefore not to beconsidered limiting of its scope, for the invention may admit to otherequally effective embodiments.

FIG. 1 illustrates a therapeutic gas delivery device having aproportional control valve and a binary control valve in series inaccordance with one or more embodiments of the present invention; and

FIG. 2 illustrates a therapeutic gas delivery device having aproportional control valve and two binary control valves in parallel inaccordance with one or more embodiments of the present invention.

DETAILED DESCRIPTION

Before describing several exemplary embodiments of the invention, it isto be understood that the invention is not limited to the details ofconstruction or process steps set forth in the following description.The invention is capable of other embodiments and of being practiced orbeing carried out in various ways.

Although specific reference is made to nitric oxide delivery devices, itwill be understood by a person having ordinary skill in the art that themethods and devices described herein may be used to deliver othermedical or therapeutic gases. Exemplary gases that may be administeredinclude, but are not limited to, nitric oxide, oxygen, nitrogen, andcarbon monoxide. As used herein, the phrase “therapeutic gas” refers togas used to treat diseases or medical disorders in a patient.

If nitric oxide is used as the therapeutic gas, exemplary diseases ordisorders that may be treated include persistent pulmonary hypertensionof the newborn (PPHN), pulmonary arterial hypertension (PAH), chronicobstructive pulmonary disease (COPD), bronchopulmonary dysplasia (BPD),chronic thromboembolic pulmonary hypertension (CTE), idiopathicpulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS) orpulmonary hypertension (PH), or nitric oxide may be used as anantimicrobial agent.

Provided are methods and devices for administering therapeutic gas to apatient that utilize both binary and proportional control valves. Thesedevices can provide enhanced dose ranges for both continuous constantconcentration delivery and single pulse per breath delivery.

As used herein, a “binary control valve” refers to a control valvehaving at least two states, the first state being completely closed andthe second state being substantially open. Examples of such valvesinclude, but are not limited to, solenoid valves and piezoelectricvalves. Binary valves with large flow-through opening area (low pressuredrop) to small diameter orifice (high pressure drop) are envisioned.Such valves generally provide a constant flow of gas when open,depending on the upstream pressure. In combination with a pressureregulator, these valves can provide a known, constant flow rate orpulsed volume of gas in proportion to the upstream pressure.

A “proportional control valve” as used herein is a valve that canprovide a variable flow rate of gas. Unlike a binary control valve, aproportional control valve can have a variable opening to provide analmost infinite number of flow rates between the completely closed stateand the completely open state. Over some portion of the control rangethese valves act in a linear region of flow output verses current input.They can be configured to control flow or pressure depending on theintegration of the sensing device.

Accordingly, one aspect of the present invention relates to atherapeutic gas delivery device having at least one binary control valveand at least one proportional control valve. The binary control valvemay be in series with the proportional control valve, or it may be inparallel with the proportional control valve. If more than one binarycontrol valve and/or proportional control valve is present, the variousvalves may be arranged in multiple configurations with combinations ofvalves in series and in parallel.

FIG. 1 shows an exemplary nitric oxide delivery device 100 having thebinary and proportional control valves in series. A source oftherapeutic gas containing nitric oxide may include gas storage cylinder103. Exemplary cylinders may contain NO in a carrier gas such asnitrogen, with a NO concentration ranging from 1 ppm to 20,000 ppm, suchas from 5 ppm to 10,000 ppm, or from 10 ppm to 5,000 ppm. In one or moreembodiments, the cylinder has a high nitric oxide concentration, such asabout 2440 ppm or about 4880 ppm. In other embodiments, the cylinderconcentration is about 800 ppm.

Instead of a cylinder storing gas comprising NO, a nitricoxide-releasing agent such as nitrogen dioxide (NO₂) or a nitrite salt(NO₂) may be used with appropriate reducing agents or co-reactants toprovide a flow of NO. For example, gas storage cylinder 103 couldcontain NO₂ gas in a concentration ranging from 1 ppm to 20,000, and thedevice can utilize an appropriate reaction to convert the NO₂ to NObefore administering to the patient.

Gas storage cylinder 103 is in fluid communication with conduit 105,which carries the therapeutic gas from gas storage cylinder 103 to thenitric oxide delivery device. The conduit 105 may be in fluidcommunication with a nasal cannula or other nasal or oral breathingapparatus 113 for delivering the therapeutic gas to the patient. Inaddition, conduit 105 may comprise a gas hose or tubing section, apressure regulator, a delivery manifold, etc. Although specificreference is made to nasal cannulas, other types of nasal or oralbreathing apparatuses may be used, such as breathing masks orendotracheal tubes.

One or more proportional control valves 107 regulate the flow oftherapeutic gas through the conduit 105 to the patient, as well as oneor more binary control valves 109. Although proportional control valve107 is shown upstream of binary control valve 109 in FIG. 1, having thebinary control valve 109 upstream of and in series with the proportionalcontrol valve 107 would be an equivalent configuration. In someembodiments, if the proportional control valve 107 is pressure-assistedopen, it may need to be upstream of the binary control valve 109.

In addition to or as an alternate to the proportional control valve 107,a variable pressure regulator may be placed upstream of the binarycontrol valve 109. A variable pressure regulator may act to control ormaintain a known volume at a fixed pressure. Such a variable pressureregulator can vary the output pressure, thus varying the flow rate ofthe downstream binary control valve 109 and extending the dynamic rangeof the binary control valve 109. The variable pressure regulator may beelectronically controlled by the control system of the nitric oxidedelivery device.

In some embodiments, a pressure sensor 108 may be placed downstream ofthe proportional control valve 107 and upstream of the binary controlvalve 109. The combination of the proportional control valve 107 and thepressure sensor 108 may act as a variable pressure regulator to controlpressure upstream of the binary control valve 109 because theproportional control valve 107 may control input flow to achieve thedesired pressure at pressure sensor 108.

In some embodiments, a “known compressed gas volume” is measured by thepressure sensor 108 upstream of the binary control valve 109. In FIG. 1,the known compressed gas volume would be the volume of compressed gas inconduit 105 between the proportional control valve 107 and binarycontrol valve 109. The portion of conduit 105 downstream fromproportional control valve 107 and upstream of binary control valve 109defines a chamber, and knowing the volume and pressure of this chamberallows the proportional control valve 107 to control the flow ratethrough the binary control valve 109.

A passageway 111 is in fluid communication with the conduit 105 whichconnects a patient trigger sensor 119 to the conduit 105. The patienttrigger sensor 119 is a pressure or flow sensor. The signal from thetrigger sensor 119 may be further processed via hardware and/or softwarelogic by a control system comprising a central processing unit (CPU)115. The trigger sensor 119 detects when a patient begins inspirationand/or expiration, and may provide that information to the controlsystem.

In some embodiments, the trigger sensor 119 may be used to determine thepatient's inspiration by detecting a negative pressure caused by thepatient's breathing effort. This negative pressure may be measuredbetween two reference points, such as between the passageway 111 and adifferential pressure port on the nitric oxide delivery device (notshown). As passageway 111 is in fluid communication with the conduit105, which in turn is in fluid communication with the patient, thepressure in passageway 111 will drop when a small sub atmosphericpressure in the patient's nose or mouth is created as the patient beginsinspiration.

Similarly, the patient trigger sensor 119 may detect the patient'sexpiration by detecting a positive pressure caused by the patient. Insome embodiments, this positive pressure differential is the amount bywhich the pressure in passageway 111 exceeds the pressure at thedifferential pressure port.

The nitric oxide delivery device 100 may comprise a control systemincluding one or more CPUs 115. The CPU 115 may be in communication witha user input device 117. This user input device 117 can receive desiredsettings from the user, such as the patient's prescription (in mg/kgideal body weight, mg/kg/hr, mg/kg/breath, mL/breath, cylinderconcentration, delivery concentration, pulse duration, etc.), thepatient's age, height, sex, weight, etc. In one or more embodiments,user input device 117 comprises a display and a keyboard and/or buttons,or may be a touchscreen device.

The CPU 115 may also be in communication with a flow sensor 121, whichmeasures the flow of therapeutic gas through proportional control valve107 and binary control valve 109. The CPU 115 can be coupled to a memory(not shown) and may be one or more of readily available memory such asrandom access memory (RAM), read only memory (ROM), flash memory,compact disc, floppy disk, hard disk, or any other form of local orremote digital storage. Support circuits (not shown) can be coupled tothe CPU 115 to support the CPU 115, sensors, control valves, etc. in aconventional manner. These circuits include cache, power supplies, clockcircuits, input/output circuitry, subsystems, power controllers, signalconditioners, and the like.

The CPU 115 of control system may be in communication with theproportional control valve 107, the binary control valve 109, thepatient trigger sensor 119, the flow sensor 121 and the pressure sensor108. When the patient trigger sensor 119 determines that a patient isbeginning inspiration, the CPU 115 sends a signal to one or both of thecontrol valves 107 and 109 to open the control valves to delivertherapeutic gas.

Depending on the particular NO administration regimen, the controlvalves 107 and 109 can operate in a number of different ways. Forexample, if one or more pulses of therapeutic gas are to be administeredin a breath, the proportional control valve 107 can be set to a certainopening and the binary control valve 109 can be used to provide thepulses of therapeutic gas. In this way, the proportional control valve107 may act as a variable sized orifice to control the flow through thebinary control valve 109. The opening of the proportional control valve107 may be increased or decreased from one breath to the next, dependingon the flow rate desired for the binary control valve 109. In oneexample, a first breath may use the proportional control 107 valve at75% of the maximum opening, and a subsequent breath may use theproportional control valve 107 at 50% of the maximum opening. Thiscombines the advantages of both valves in that the flow rate can bevaried with the proportional control valve 107, and at the same time thesystem utilizes the fast response time and precision of the binarycontrol valve 109.

This operation of the proportional control valve 107 and the binarycontrol valve 109 can be useful for many administration schedules. Onesuch administration schedule is one that varies the amount of NOadministered to the patient each breath. A desired total amount of drugcan be set by a user, such as an amount of NO to be provided perkilogram of ideal body weight per hour (mg/kg IBW/hr). A patient's idealbody weight is a function of a patient's sex and height. The deviceadjusts the amount of drug given per breath so that the amount deliveredis independent of the patient's respiratory rate. The binary andproportional control valve configuration in FIG. 1 can provide a largerrange of doses per breath by allowing the flow rate to change, ratherthan solely relying on varying the time that the valve is open. This canbe particularly important if the timing or duration of the NO pulse iscritical. Accordingly, in some embodiments, one or more pulses oftherapeutic gas are provided in the first half of inspiration or firstthird of inspiration.

The memory may store a set of machine-executable instructions (oralgorithms) for calculating the desired volume of the gas pulse and thepulsing schedule to achieve a particular patient prescription. Forexample, if the patient's breathing rate and the cylinder concentrationare known, then the CPU 115 can calculate how much volume of therapeuticgas needs to be administered each breath or set of breaths to providethe desired dosage of nitric oxide. The memory may also record the timethat the binary control valve 109 is open during each pulse, so thatfuture calculations can take into account how much nitric oxide haspreviously been administered.

In some embodiments, the memory may store a set of machine-executableinstructions (or algorithms), when executed by the CPU 115, cause thedelivery device to perform a method comprising: sensing inspiration of apatient with a trigger sensor, delivering a pulse of therapeutic gascontaining nitric oxide to the patient during inspiration, monitoringthe patient's respiratory rate or changes in the patient's respiratoryrate, and varying the quantity (e.g. volume or mass) of therapeutic gasdelivered in a subsequent breath. The machine-executable instructionsmay also comprise instructions for any of the other methods describedherein.

The valve configuration in FIG. 1 can also be used for administrationschedules that provide a constant pulse volume or dose each breath, i.e.mL/breath, nmol/breath, ng/breath, etc. Here, a single device can beused for patients with a wide range of dose requirements because theproportional control valve 107 can be used to set the flow rate orsupply pressure to the binary control valve 109. Accordingly, even ifthe flow rate does not change during a single patient's therapy, thedevice can still provide a range of doses for mL/breath having the samepulse width (i.e. length of pulse) and one device can be used forpatients having different prescriptions. Furthermore, it may bedesirable to change a given patient's therapy amount from one mL/breathamount to a different mL/breath amount as the patient's respiratorypattern changes. For example, a patient may require one dose ofmL/breath when awake and a higher dose of mL/breath when asleep so thatthere is not a large variation in amount of drug delivered per hour orother time period.

Thus, the combination of a binary control valve and a proportionalcontrol valve can widen the dosing range capability or provide moreprecise control of NO delivery pulse timing to a patient.

The binary control valve and proportional control valve may also be in aparallel configuration, such as the one shown in FIG. 2. In FIG. 2,nitric oxide delivery device 200 has a proportional control valve inparallel with binary control valves 209 and 210. As with the device inFIG. 1, the nitric oxide delivery device 200 may be connected to atherapeutic gas source 203 that provides a supply of nitric oxide or anitric oxide-releasing agent. Conduit 205 splits into three parallelflow paths, with each flow path having a different control valve (207,209, 210) and its own flow sensor (221, 223, 225). More or fewerparallel flow paths may be used, and binary and proportional controlvalves may be combined in the same flow path. Furthermore, it is notnecessary for each flow path to have its own flow sensor if a flowsensor is placed downstream of the convergence of the parallel flowpaths or upstream of the divergence of the parallel flow paths.

A control system comprises a CPU 215 which may be in communication witheach control valve (207, 209, 210) and each flow sensor (221, 223, 225).The CPU 215 may also be in communication with user input device 217. CPU215 and user input device 217 may have any of the features describedabove for CPU 115 and user input device 117 in FIG. 1.

In FIG. 2, the nitric oxide delivery system 200 delivers therapeutic gasto a patient using a ventilator 237. Flow sensor 227 measures the flowof breathing gas from the ventilator 237 through the inspiratory limb231 and sends a signal to CPU 215. CPU 215 then opens one or morecontrol valves (207, 209, 210) to provide a flow of therapeutic gasthrough conduit 205, which is combined with the breathing gas ininjector module 229. The CPU 215 provides a flow of therapeutic gas thatis proportional (also known as ratio-metric) to the breathing gas flowrate to provide a desired concentration of NO in the combined breathinggas and therapeutic gas. The combined therapeutic gas and breathing gasis then delivered to the patient via patient limb 235, and the patient'sexpiratory gases are carried through the expiratory limb 233 to theventilator 237. Although flow sensor 227 is shown as within injectormodule 229, it may also be placed elsewhere in the inspiratory limb 231,such as upstream of the injector module 229. Also, instead of a flowsensor 227, the CPU 215 may receive a signal directly from theventilator 237 indicating the flow of breathing gas from the ventilator237.

The two configurations shown in FIG. 1 and FIG. 2 are only two examplesof therapeutic gas delivery devices utilizing binary and proportionalcontrol valves. Other configurations can include, but are not limitedto:

-   -   a. two or more parallel flow paths, with each flow path having        at least one binary control valve and at least one proportional        control valve in series;    -   b. two or more parallel flow paths, with one or more flow paths        having at least one binary control valve and at least one        proportional control valve in series and one or more other flow        paths having only a binary control valve or only a proportional        control valve;    -   c. two or more parallel flow paths, with one or more flow paths        having a binary control valve and one or more flows path having        a proportional control valve; and    -   d. a binary control valve in series with two or more        proportional control valves in parallel flow paths.

One of ordinary skill in the art can envision other combinations ofbinary and proportional control valves in parallel and/or in series inaccordance with the present invention. Furthermore, any of theconfigurations described herein may utilize a variable pressureregulator, either in addition to or as an alternative to a proportionalcontrol valve. For example, instead of a proportional control valve anda binary control valve in series, a variable pressure regulator placedupstream of the binary control valve may provide the same effect.Additionally, instead of configurations that have a binary control valvein parallel with a proportional control valve, two binary control valvesmay be in series with either one or both binary control valves having avariable pressure regulator upstream. A variable pressure regulator mayalso be used with a proportional control valve. In some embodiments, thevariable pressure regulator comprises a proportional control valve and apressure sensor.

In any of the configurations, if more than one binary control valve isused, they may have the same or different flow rates. It may beadvantageous to have one binary control valve deliver at a higher flowrate than another binary control vale, such as having one binary controlvalve deliver at 6 L/min and another binary control valve deliver at 1L/min. According to one or more embodiments, at least two binary controlvalves are used that have a flow rate ratio of the low flow rate valveto the high flow rate valve in the range from about 1:2 to about 1:10.

Similarly, if more than one proportional control valve is used, they mayhave the same or different flow ranges. For example, a firstproportional control valve may have a flow rate range from 0.1 to 10L/min and second proportional control valve may have a flow rate rangefrom 0.005 to 1 L/min. Such an arrangement can maximize the accuracy ofthe therapeutic gas flow delivered by using the optimum working rangesfor each proportional control valve, i.e. not using the extreme high endor the extreme low end of the working range for the valve.

In some embodiments, whether the control system will use one of thebinary control valves (209, 210) or the proportional control valve (207)to deliver the therapeutic gas may depend on the therapeutic gas demand.The “therapeutic gas demand” is the amount of therapeutic gas requiredto provide the set NO in the combined flow of breathing gas andtherapeutic gas. The therapeutic gas demand will vary based on theconcentration of NO in the therapeutic gas, the set NO concentration andthe flow rate of the breathing gas. If the cylinder concentration is 800ppm NO and the breathing gas flow rate is 10 L/min, then approximately0.5 L/min of therapeutic gas is required to provide a deliveryconcentration of 40 ppm. Accordingly, the therapeutic gas demand is 0.5L/min for this combination of cylinder concentration, breathing gas flowrate and delivery concentration. When the therapeutic gas demand is asmall fraction of the maximum therapeutic gas flow rate for theproportional control valve 207, the proportional control valve 207 maynot deliver therapeutic gas with the same precision as with highertherapeutic gas demands. If the maximum therapeutic gas flow of theproportional control valve 207 is 6 L/min, then therapeutic gas demandsless than 1 or 2% of this amount (i.e. less than 0.06 or 0.12 L/min) maynot be accurately delivered with continuous flow through theproportional control valve 207. Thus, it may be advantageous to pulseeither the proportional control valve 207 or one or more of the binarycontrol valves (209, 210) at these low therapeutic gas demands. Althoughthis pulsing technique may not result in continuous real-timetherapeutic gas delivery that is proportional to the breathing gas flow,it can provide a “baseline” average concentration of NO. This pulsingtechnique may be especially useful when the ventilator 237 is outputtinga low bias flow or when the nitric oxide delivery device is being usedwith a nasal cannula providing a low flow rate of oxygen to a patient.

Furthermore, in one or more embodiments, one or more proportionalcontrol valves may be used to deliver a pulse or pulses of NO. Suchpulse or pulses of NO may be used to approximate a constantconcentration dose of NO over a breath cycle. A device that uses suchproportional control valve(s) to provide pulse(s) of NO may incorporateone or more binary control valves as described above, or may includeonly one or more proportional control valves for regulating the flow ofNO. As described above, if more than one proportional control valve isused, they may have the same or different flow ranges. The device mayalso provide pulses of gas through the proportional valves at certainflow rates (such as lower flow rates) and provide a continuous flow ofgas at other flow rates (such as higher flow rates).

Accordingly, in some embodiments, the CPU 215 uses the proportionalcontrol valve 207 at higher therapeutic gas demands and one or more ofthe binary control valves (209, 210) at lower therapeutic gas demands.In some embodiments, the delivery device 200 delivers a continuous flowof therapeutic gas through the proportional control valve 207 when thetherapeutic gas demand is greater than 0.1% of the delivery range of theproportional control valve 207, such as when the therapeutic gas demandis greater than or equal to the following percentages of the deliveryrange: 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15 or 20% Likewise, insome embodiments, the delivery device delivers one or more pulses oftherapeutic gas through the binary control valve 209 or 210 when thetherapeutic gas demand is less than 20% of the delivery range of theproportional control valve 207, such as when the therapeutic gas demandis less than or equal to the following percentages of the deliveryrange: 15, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5 or 0.1%.Alternatively, the delivery system 200 may pulse through theproportional control valve 207 when the demand is less than or equal toany of the previous percentages, or the delivery system may pulsethrough a binary control valve and proportional control valvecombination that is in series when the therapeutic gas demand is low.

It is not necessary to use the nitric oxide delivery device 100 in FIG.1 for single pulse per breath delivery (i.e. mg/kg IBW/hr or mL/breath)or use the nitric oxide delivery device 200 in FIG. 2 for constantconcentration (either by repeatedly pulsing any of the control valves orcontinuously flowing through the proportional control valve). Indeed,any of these methods of nitric oxide delivery may use multiple binaryand proportional control valves in parallel, in series, or combinationsof both. Depending on the desired nitric oxide therapy, any of thedevices described herein may have the appropriate breath trigger sensorfor detecting the breath of a spontaneously breathing patient or may beadapted to use with a ventilator. Also, reference to “single pulse perbreath” therapies encompasses methods that skip one or more breaths, inaddition to methods that deliver a pulse of therapeutic gas everybreath. It is also possible to use any of the devices described hereinfor either constant concentration dosing or pulse per breath dosing.

Another aspect of the current invention provides a method ofadministering a therapeutic or medical gas, the method comprisingproviding a therapeutic gas delivery device comprising at least onebinary control valve and at least one proportional control valve anddelivering therapeutic gas to the patient through one or more of thebinary control valve and the proportional control valve. The therapeuticgas delivery device of this method may have any of the featurespreviously described for therapeutic gas delivery devices having bothbinary and proportional control valves, such as having combinations ofthe valves in series, parallel or both. The therapeutic gas may comprisenitric oxide or a nitric oxide releasing agent. If the therapeutic gascomprises a nitric oxide-releasing agent, then it is preferablyconverted to nitric oxide prior to administering to the patient.

Reference throughout this specification to “one embodiment,” “certainembodiments,” “one or more embodiments” or “an embodiment” means that aparticular feature, structure, material, or characteristic described inconnection with the embodiment is included in at least one embodiment ofthe invention. Thus, the appearances of the phrases such as “in one ormore embodiments,” “in certain embodiments,” “in one embodiment” or “inan embodiment” in various places throughout this specification are notnecessarily referring to the same embodiment of the invention.Furthermore, the particular features, structures, materials, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It will be apparent to those skilled in the art thatvarious modifications and variations can be made to the methods anddevices of the present invention without departing from the spirit andscope of the invention. Thus, it is intended that the present inventioninclude modifications and variations that are within the scope of theappended claims and their equivalents.

What is claimed is:
 1. A therapeutic gas delivery device comprising: aninlet to connect to a source of therapeutic gas; an outlet to connect toa device that introduces the therapeutic gas to a patient; at least onebinary control valve in fluid communication with the inlet and outletthat delivers a constant flow of the therapeutic gas; at least oneproportional control valve in fluid communication with the inlet andoutlet that delivers a variable flow of the therapeutic gas, wherein thebinary control valve and the proportional control valve are in parallelflow paths; a control system that delivers the therapeutic gas throughone or more of the binary control valve and the proportional controlvalve; and wherein the control system is adapted to deliver thetherapeutic gas to a patient in an amount proportional to a flow ofbreathing gas.
 2. The therapeutic gas delivery device of claim 1,wherein the control system delivers a continuous flow of therapeutic gasthrough the proportional control valve when a therapeutic gas demand isgreater than or equal to 5% of a delivery range and delivers one or morepulses of therapeutic gas through the binary control valve when thetherapeutic gas demand is less than or equal to 1% of the deliveryrange.
 3. The therapeutic gas delivery device of claim 1, wherein thebinary control valve is a first binary control valve and the therapeuticgas delivery device further comprises a second binary control valve inparallel to the first binary control valve.
 4. The therapeutic gasdelivery device of claim 3, wherein the first binary control valve andthe second binary control valve deliver pulses of therapeutic gas atdifferent flow rates.
 5. The therapeutic gas delivery device of claim 4,wherein the ratio of the flow rate of the first binary control valve tothe flow rate of the second binary control valve is in the range fromabout 1:2 to about 1:10.
 6. The therapeutic gas delivery device of claim3, wherein the control system delivers multiple pulses per breaththrough one or more of the first binary control valve and the secondbinary control valve.
 7. The therapeutic gas delivery device of claim 1,wherein the device that introduces the therapeutic gas to the patient isin fluid communication with a ventilator.
 8. The therapeutic gasdelivery device of claim 1, wherein the device that introduces thetherapeutic gas to the patient is a nasal cannula, endotracheal tube ora face mask.
 9. The therapeutic gas delivery device of claim 1, whereinthe control system is adapted to provide a single pulse in a patient'sbreath through one or more of the binary control valve and theproportional control valve.
 10. The therapeutic gas delivery device ofclaim 1, wherein the source of therapeutic gas comprises nitric oxide ora nitric oxide-releasing agent.
 11. A method of administering atherapeutic gas to a patient, the method comprising: receiving a flow oftherapeutic gas to a therapeutic gas delivery device having at least onebinary control valve that delivers a constant flow of therapeutic gasand at least one proportional control valve that delivers a variableflow of the therapeutic gas, wherein the binary control valve and theproportional control valve are in parallel flow paths; measuring a flowof breathing gas; and delivering therapeutic gas to the patient duringinspiration through one or more of the binary control valve and theproportional control valve in an amount proportional to the flow ofbreathing gas.
 12. The method of claim 11, wherein a continuous flow oftherapeutic gas is delivered through the proportional control valve whena therapeutic gas demand is greater than or equal to 5% of a deliveryrange and one or more pulses of therapeutic gas is delivered through thebinary control valve when the therapeutic gas demand is less than orequal to 1% of the delivery range.
 13. The method of claim 11, whereinthe binary control valve is a first binary control valve and thetherapeutic gas delivery device further comprises a second binarycontrol valve in parallel to the first binary control valve.
 14. Themethod of claim 13, wherein the first binary control valve and thesecond binary control valve deliver pulses of therapeutic gas atdifferent flow rates.
 15. The method of claim 14, wherein the ratio ofthe flow rate of the first binary control valve to the flow rate of thesecond binary control valve is in the range from about 1:2 to about1:10.
 16. The method of claim 13, wherein the control system deliversmultiple pulses per breath through one or more of the first binarycontrol valve and the second binary control valve.